Effects of Nicotine on Brain Activity as Measured by fMRI The goal of this project is to investigate the pharmacodynamics of nicotine in the human brain using pharmacological MRI. These studies consist of investigating the effect of varying the rate and number of injections on neuronal activation. This year we have scanned 7 subjects for this project. Recruitment is ongoing. Effects of Nicotine on Cognitive Task Performance and Brain Activity as Measured by fMRI This project is comprised of four tasks that were designed to tax specific cognitive functions. Hypotheses about specific attentional functions modulated by nicotine drove task selection and design. All tasks are tested in smokers and non-smokers, the former on and off nicotine patches. The first task targets the attentional system and investigates one division of this system, selected vs. divided attention. In control participants, we have found several brain regions, including right middle frontal, left insular, and a trend in supplementary motor area, that are specific for the divided attention task. The second task involves separating attending to a location vs. motor planning for a location. The third task looks at central executive functioning by requiring updates and switches between two separate counts held simultaneously in working memory. Several brains regions showed greater activation in the nicotine condition, including left middle frontal gyrus and bilateral middle temporal gyrus. The fourth task was designed to differentiate between bottom-up and top-down processes of attentional resource allocation by parametrically varying the amount of advance information available concerning the location of a target stimulus. Automatic versus evaluative components of cue reactivity: This protocol aims at investigating the mechanisms by which drug-related stimuli exert their behavioral effects in dependent individuals (smokers and cocaine users). Drug-related pictures are embedded in a cognitive task that parametrically varies processing load. The degree to which the concomitantly presented drug cues can be cognitively evaluated is thereby manipulated. This allows the influence of processing depth to be elucidated on different measures of cue reactivity, including performance indices of attentional bias, subjective craving responses, psychophysiological parameters and regional brain activation. Recent theories of drug dependence postulate that drug cues exert their effects in an automatized manner in the absence of conscious control and do not depend on cue-induced craving states. Brain Activity Alterations As Measured By fMRI During Nicotine Self-Administration The overall goal of this protocol is to employ fMRI to define neural sites and mechanisms underlying nicotine self-administration (SA) in humans. Specific Aims include: a) confirmation of intravenous (IV) nicotine SA vs. placebo and dose selection, b) determination of neural activation patterns during simple SA behavior and compare the magnitude and time course of its subjective, behavioral, and CNS effects before and after IV injections, c) determine the effect of self- vs. passive- administration of nicotine on the parameters listed above, d) and determine the role that conditioned cues play in nicotine?s activation properties are examined by comparing neural activation patterns during normal SA (in which the cue presentation is accompanied by drug infusion) with those associated with response-contingent presentation of cues during extinction conditions. Neuronal Bases of Cognitive and Affective Differences in Adolescent Smokers The developmental ramifications of tobacco addiction on cognition and affective processing in adolescents are not known. There is some evidence from studies of adult smokers that nicotine can enhance cognition in the areas of attention and memory. There is also evidence that adults smoke for a ?caaaalming? effect. The effects of nicotine on adolescents are less clear. This study will examine the effects of nicotine and withdrawal from nicotine in adolescent smokers using cognitive and affective tasks that probe attention, memory, and affect. fMRI will be employed to investigate the cognitive, affective and associated brain activation changes during acute nicotine withdrawal in nicotine dependent adolescents. Adolescent smokers are studied during two states, tobacco satiation and acute tobacco withdrawal. Matched nonsmokers are also studied to provide both normative data for the cognitive and affective task performance, as well as provide control data for any time effects. Neurobiology and Pharmacokinetics of Acute MDMA Administration The overall goal of this project is to employ fMRI to define neural sites and mechanisms underlying the cognitive effects of orally administered MDMA (ecstasy) in humans. The specific aims are to a) determine the sites and time-course of MDMA-induced neural activation, b) determine the effect of MDMA on decision making and its neural correlates through the use of a gambling task in the fMRI, c) determine the effect of MDMA on semantic processing during a semantic task and the neural correlates of these processes, c) determine the effect of MDMA on affective processing and its neural correlates using an picture based affective rating task, d) determine the effects of MDMA on incidental verbal learning using the Rey Auditory Verbal Learning Task, e) determine the effects of MDMA administration on attention using the Attention Network Task. The Effects of Expectation on Natural and Drug-Induced Rewards This protocol will compare cocaine dependent and drug naive control participants on various aspects of response to reward cues and reward receipt. fMRI will be used to assess neuronal response, while rating scales will be used to assess subjective responses. The first experiment will use the natural reward of a small squirt of flavored liquid. A visual or olfactory stimulus will cue the coming reward. Occasionally, the reward will be delayed or the ?wrong? reward will be delivered, thus violating the expectation of the participant. It is hypothesized that the nucleus accumbens will show changes in activity when reward expectations are violated and that these changes will be less pronounced in cocaine dependent participants. The second experiment will deliver a drug-induced reward in the form of 15 mg/70kg of methylphenidate. Participants will be cued as to what they will receive with a word on a screen followed by a bar shrinking over time. In four separate sessions, participants will be cued twice that they will receive methylphenidate and twice that they will receive saline. One saline cue and one methylphenidate cue will be inaccurate (i.e., they will receive saline when cued to receive methylphenidate and vice versa). Reward processing in cocaine dependent individuals before and after cocaine self-administration Participants in this study will include a sample of non-treatment seeking adults with a diagnosis of cocaine dependence and a sample of healthy, matched controls. Participants will be asked to undertake two experimental paradigms, each of which is designed to ascertain different aspects of reward processing, while undergoing functional MRI. The first task will be modification of Knutson?s Monetary Incentive Delay task, which measures aspects of incentive salience, and the second will be a modification of McClure?s passive conditioning task, which examines the prediction of errors in reward delivery. Both aspects of reward processing that we plan to investigate have been linked to aspects of dopamine (DA) function in normal healthy adults. Moreover, the brain regions that have been shown to support these functions have also been shown to exhibit functional abnormality in substance abusing individuals.